Glioblastoma (GBM) is a primary malignancy of the central nervous system (CNS) that is universally fatal, extremely difficult to treat, and associate with tremendous burden to patients and caregivers due to the loss of neurological function. Aspects of the disease biology are being unraveled particularly the driver oncogenic events associated with the disease and the molecular subtypes. All reveal a complex tapestry suggesting downstream events of the classifying signatures are promoting a condition of extreme genomic instability. Our understanding of this altered state is limited and not in concordance with what biology teaches us, that this level of chromosomal instability should lead to mitotic catastrophe and cell death. Instead, we see a state of disease promotion and progression. We have reported on alterations occurring in the evolutionarily conserved cellular organelle, the centrosome induced by phosphoregulation of a RNA-binding protein, HuR (Human Antigen R). Aberrant regulation of HuR induces centrosome amplification, aneuploidy, and disease progression. It is our hypothesis that cytoplasmic localization and multimer formation drives the oncogenic behavior of HuR. We believe that insights into this novel area of regulation will provide insights into the mechanisms of genomic instability in cancer. We have proposed three specific aims to determine the importance of post-transcriptional regulation of centrosomes in the promotion of chromosomal instability. In Aim 1, we will extend our initial mechanistic insights to dissect the control mechanisms through which multimerization of HuR promotes instability with resultant tumor progression. In the second aim, we will develop compounds identified that have the capacity to alter HuR function specifically the acquisition of the states of cytoplasmic localization and multimer formation. In the last aim, we will characterize the impact of HuR inhibition in primary GBM cell lines in vitro and in vivo.